Mo Hazard Ratio Research Articles

Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer

BackgroundOCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC).AimsThe main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC).MethodsIn total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power).ResultsThe majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm.DiscussionOCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option.Trial registrationISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018.

Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer: A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24.

5505 Background: Standard treatment of platinum-sensitive recurrent ovarian cancer (PSROC) is platinum based combination chemotherapy ± bevacizumab. However, this treatment modality is hardly curative, and is associated with significant toxicity. Both bevacizumab (BEV) and PARP inhibitors (PARPi) have demonstrated efficacy in PSROC. There is preclinical evidence of enhanced activity of the combination. This is the proof-of-concept randomized trial of PARPi-BEV combination against PARPi monotherapy as treatment in PSROC, regardless of number of previous lines of therapies. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and BEV 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was progression-free survival (PFS). Stratification was according to homologous recombination-deficiency(HRD) status (MyChoice HRD) and chemotherapy-free-interval (CFI)(6-12months (mo) vs. >12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: median 11.9 vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.35; 95% confidence interval (CI),[0.21 to 0.57]; P<0.001. Pre-planned exploratory subgroup analyses: patients with HRD-positive tumors (n=54) HR 0.36 (CI, 0.18-0.69); HRD-negative disease (n=43) HR, 0.47 (CI, 0.24-0.95); g BRCAmut patients (n=34) HR 0.53 (CI, 0.23-1.21); non-g BRCAmut patients (n=63) HR 0.33; CI, 0.18-0.61); CFI of 6 to 12 mo (n=38) HR, 0.29 (CI, 0.14 to 0.62); CFI of ≥12 mo (n=59) HR, 0.42; (CI, 0.22 to 0.80). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (26.5% vs. 0%) and neutropenia (12.2% vs. 2.1%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Both niraparib alone and the combination had meaningful activity in PSROC. Compared to niraparib alone, the chemotherapy-free regimen of niraparib and BEV significantly improved PFS in women with PSROC,regardless of HRD status and duration of CFI. Clinical trial information: NCT02354131.

1141P - Percutaneous Hepatic Perfusion (CHEMOSAT® or CS-PHP) of Melphalan vs. Best Alternative Care (BAC) in Patients (PTS) with Hepatic Metastases from Melanoma: Update of a Randomized Phase 3 Study

ABSTRACT Background CS-PHP (CHEMOSAT®; Delcath Systems Inc, New York, NY) is a regional therapy which isolates and perfuses the liver with high-dose chemotherapy. Unwanted systemic exposure is minimized by extracorporeal filtration of hepatic venous blood. Methods A prospective randomized multicenter phase 3 study compared CS-PHP of melphalan with BAC in pts with proven unresectable hepatic metastases from ocular or cutaneous melanoma. A survival update was performed on 31 March 2011. CS-PHP melphalan 3.0 mg/kg ideal body weight was infused into the hepatic artery over 30 min with concurrent extracorporeal filtration for 60 min. Up to 6 treatments were given every 4–8 wks. In the BAC group, crossover to CS-PHP melphalan was permitted after hepatic disease progression. The primary endpoint was investigator-assessed hepatic progression-free survival (hPFS). An exploratory post-hoc analysis of pts who crossed from BAC to CS-PHP vs. BAC-only pts was also performed. Results 93 pts were randomized to CS-PHP (n = 44) or BAC (n = 49). After hepatic disease progression, 28 pts crossed over to CS-PHP. Results are shown in the Table. The most common grade 3/4 toxicities in CS-PHP pts (n = 40) were hematological peri-procedural thrombocytopenia (73%) and anemia (55%) and post-procedural (beyond day 4 post-treatment) neutropenia (93%) or thrombocytopenia (83%). The safety profile in crossover pts was similar to that in pts randomized to CS-PHP melphalan. Conclusions CS-PHP melphalan significantly prolonged hPFS compared with BAC in pts with liver-dominant metastatic melanoma, thereby meeting the primary study objective. Efficacy was similar after hepatic disease progression in BAC-CS-PHP crossover pts as in those randomized initially to CS-PHP. Treatment group n Median hPFS, mo Hazard ratio (95% CI) Median OS, mo Hazard ratio (95% CI) CS-PHP 44 8.0 0.35 (0.23-0.54) 9.8 1.08 (0.69-1.68) BAC 49 1.6 P 9.9 NS BAC only 21 1.6 0.32 4.1 0.33 BAC → CS-PHP crossover 28 8.8 15.3 Disclosure All authors have declared no conflicts of interest.

IMPACT OF EARLY VERSUS LATE MICROVASCULAR OBSTRUCTION ASSESSED BY MAGNETIC RESONANCE IMAGING ON LONG-TERM OUTCOME AFTER ST-ELEVATION MYOCARDIAL INFARCTION

Results: Early MO was present in 330 patients (79%) and late MO in 292 (70%). In multivariable Cox regression analysis adjusting for TIMIrisk score, ejection fraction (EF) and infarct size, the presence and extent of late MO were independently associated with the composite primary endpoint. At a hazard ratio (HR) of 2.73 (95%CI 1.16-6.42, p=0.022) the presence of late MO was identiied as the strongest independent predictor for the occurrence of the composite endpoint (TIMI-risk score HR 1.22 95%CI 1.08-1.37, p=0.001; extent of MO HR 1.12 95%CI 1.03-1.22, p=0.009; EF HR 0.97 95%CI 0.95-0.99, p=0.022; infarct size p=0.26). In a second multivariable Cox regression analysis again adjusting for TIMI-risk score, EF and infarct size the presence and extent of early MO were not independently associated with the primary endpoint (presence of early MO p=0.75; extent of early MO p=0.89; TIMI-risk score HR 1.13 95%CI 1.00-1.29, p=0.05; EF HR 0.97 95%CI 0.95-1.00, p=0.022; infarct size p=0.51). Conclusion: In contrast to early MO, the presence and extent of late MO are strong independent predictors for the occurrence of death, non-fatal myocardial reinfarction and congestive heart failure after STEMI.